Project Summary: There is an inverse relationship between cancer and neurodegenerative disease. Specifically, people with Alzheimer?s disease have a lower risk of cancer and vice versa. While there is evidence that immune function underlies the relationship between non-brain cancer and neurodegenerative disease, we hypothesize that there is a different cause for this inverse relationship in brain cancers. We believe proteostasis lies at the core of this relationship for brain cancer. We believe toxic peptides associated with neurodegenerative diseases cause the cells expressing or containing them to have a decreased ability to produce and maintain functional proteins. This would mean that these cells with these toxic peptides would have lower effective dosages of oncogenes. Alzheimer?s disease (AD) and other dementias are increasingly thought of as diseases of protein misfolding. Accordingly, much research has found that treatments that increase cells? abilities to manage misfolded or aggregated proteins tend to decrease the severity of AD-related phenotypes in model systems. Overexpression of chaperones tends to suppress AD-related pathologies. Conversely, cancer is a disease wherein oncogene expressing cells that manage misfolded proteins better, tend to comprise more aggressive tumors. Therefore, managing misfolded proteins is good for the progression of cancer and bad for the progression of AD and other neurodegenerative diseases where aggregate management currently seems to be a critical component of the diseases. Thus, there is an antagonistic role for proteostasis in cancer and AD. AD and other neurodegenerative disorders cause a significant burden to the proteostatic systems. We believe that it is this burden that decreases the proteostatic capacities of cells in the brain, and is the cause of the inverse relationship between AD and various brain cancers, especially glioblastoma, where Ras is a critical component. We believe this because increased chaperone capacity, which begets increased general proteostasis causes more severe neoplasia formation in our animal model of Ras-based cancer. Additionally, higher expression of chaperones decreases the severity of phenotypes caused by toxic peptides (A?, Tau and ?-synuclein) in the same animal model system. In the proposed research, we aim to understand how toxic peptides associated with neurodegenerative diseases affect Ras-driven neoplasia formation. Conversely, we will determine how phenotypes caused by these same toxic peptides are changed by nullification or overexpression of chaperones that we have found to modulate Ras-driven neoplasia formation in our currently funded research designed to understand what factors cause the incomplete penetrance of neoplasia formation. Thus, in the proposed research we will take a genetic approach to understand the inverse relationship between brain cancer and neurodegenerative disease.